Lipoxygenases are a class of enzymes which are involved in the metabolism of arachidonic acid. Said acid is converted to biologically active leukotrienes, which are involved in inflammatory reactions. Lipoxygenases therefore play a role, for example, in asthma and some cancers as they are overexpressed by some tumours. The subsequent inflammatory reaction causes new blood vessels to form (angiogenesis) such that the tumour is able to build up an independent blood supply and generate metastases.
Inhibiting lipoxygenase is therefore of central importance for suppressing the breakdown of arachidonic acid and for minimising the subsequent inflammatory reactions.
The inhibition of 5-lipoxygenase, also referred to as 5-LO or 5-LOX, is of particular importance.
There are currently only a few drugs on the market which inhibit lipoxygenase. Many previous candidates from clinical studies failed due to excessively low bioavailability and high metabolic breakdown and an associated low level of in vive activity.
As described in a publication by Mano et al. [T. Mano, K. Mlyamoto, Bioorg. Med. Chem., 2003, 11, 3,879-3,887], experiments with imidazole derivatives have already been carried out in order to improve the solubility behaviour of 5-LOX inhibitors. However, the syntheses for these derivatives are very complex, thus making them very expensive to prepare. At the same time, some of the compounds lose a great deal of their effectiveness within the organism as they are metabolically extremely unstable.
It is known that dicarba-closododecaboranes (also carbaboranes or carboranes, C2B10H12) are non-toxic [M. S. Koo, S. B. Kahl, J. Med. Chem., 2007, 50, 820-827] and chemically and metabolically extremely stable compounds [Z. J. Lesnikowski, Collect. Czech. Chem. Commun., 2007, 72, 1,646-1,658]. Furthermore, it has already been demonstrated that the use of carboranes in drugs may lead to increased metabolic stability [M. L. Beer, J. Lemon, J. F. Valliant, J. Med. Chem., 2010, 53, 8,012-8,020; J. F. Valliant, P. Schaffer, K. Stephenson, CA 2348853 A1].
CA 2348853 A1 discloses a compound, an analogue of tamoxifen, in which one of the three phenyl rings is replaced by a carborane cluster, the cluster having a mono-functionalisation. The cluster analogue demonstrates pharmacological activity for breast cancer therapy and can be used, inter alia, in boron neuron capture therapy (BNCT).
WO 2008/145733 describes, inter alia, the substitution of aromatic ring structures within particular compounds by boron-containing clusters, preferably carboranes, in order to thus achieve improved pharmaceutical properties. Disclosed is a method for preparing ortho-substituted carboranes which assume the position of ortho-substituted phenyl rings within known compounds, such as salicylic acid. However, the drawback to these ortho-carboranes is that they have high metabolic instability and restricted effectiveness. The mentioned compounds are intended to be used for improved inhibition of cyclooxygenase; however, inhibition tests on the enzyme or cytotoxicity tests have not been carried out and demonstrated. No evidence has been provided for the effectiveness of the substances either. Meta- and para-carboranyl compounds are cited as carboxylic acids and carboxylic acid chlorides known in the literature; however, these compounds have no structural similarity to inhibitors or precursors of inhibitors of lipoxygenase or the lipoxygenase pathway. The subsequent conversion to compounds having LOX-inhibiting properties was not sought after or investigated in WO 2008/145733.
WO 20061073938 describes, inter alia, the use of boron clusters which are mono-functionalised, i.e. only substituted at one position, for substituting indolizine rings in compounds which, as anti-bacterial, inflammation-inhibiting and anti-viral compounds, are intended to be effective in particular against HIV.
The drawback to mono-functionalised clusters is that they have only insufficient cytotoxicity towards various cancer cell lines.
Publications by W. Neumann et al. illustrate the introduction of tertiary alcohol substituents on the carborane frame which are in ortho positions in relation to already present substituents. In this case, a carboxylic acid unit introduced on the carborane frame is reduced/alkylated two-fold by means of alkyl lithium. [W. Neumann, Dalton Trans., 2014, 43, 4,935-4,937; W. Neumann, Dalton Trans., 2015, 44, 6,638-6,644]. The drawback is that only ortho-substituted carborane frames can be generated on this pathway. No primary or secondary alcohols can be generated in this way either, which considerably restricts the applicability of the synthesis. The subsequent conversion to compounds having LOX-Inhibiting properties was not investigated in the publications.